PD-1/PD-L1 blockade in cancer treatment: perspectives and issues

Abstract

Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.

Keywords: Biomarker; Immunotherapy; Nivolumab; PD-1; PD-L1; Value.

Fig. 1

Programmed death (PD)-1 inhibitors in cancer. PD-1 inhibitors (anti-PD-1 antibody and anti-PD-L1 antibody) block PD-1/PD-L1 signaling and induce anti-tumor immune reactivation at two checkpoints: cognitive phase (lymph node) and effector phase (tumor microenvironment). αPD-1 Ab anti–PD-1 antibody, αPD-L1 Ab anti–PD-L1 antibody

Fig. 2

Relationship between PD-1 signal and genomic mutation. Mutated neo-antigens are expressed on the surface of a cancer cell in response to genomic mutation and amplification of a cancer cell. Recognition of a neo-antigen as a foreign body by an antigen-presenting cell (APC) induces a T-cell response, and consequently the activated T cell releases interferon (IFN)-γ. A cancer cell that is exposed to IFN-γ expresses PD-L1, thereby establishing an acquired immune resistance. In this type of tumor microenvironment, a PD-1 pathway inhibitor should be effective; thus, genome-wide mutation analysis (i.e., mutanome analysis) of cancer cells using next-generation sequencing technology and diversity analysis of the T-cell repertoire (i.e., the immunome) have attracted attention as strategies for identification of predictive biomarkers. APC antigen-presenting cell

Fig. 3

Identification of the best biomarker strategy. A combination or algorithm of biomarkers may be needed. For example, it is important to understand whether it will be necessary to use a combination of biomarkers, e.g., PD-L1+ tumor cells, PD-L1+, and/or PD-1+ tumor-infiltrating lymphocytes, frequencies of neo-antigens and tumor mutations, and diversity of the T-cell repertoire. Additionally, more candidate predictive biomarkers will be identified in the future. Therefore, development of an algorithm or combination of these biomarkers should be a high priority for future work

Fig. 4

Perspectives and issues regarding PD-1 inhibitors. Asterisk TR translational research, double asterisk rTR reverse translational research. Section sign See reference [89]